The capacity to assay hematopoietic committed stem cells in humans and factors which regulate their growth allows us to investigate normal and abnormal hematopoiesis in vitro and in vivo. We believe that defects in negative feedback regulation of granulocytic-monocytic stem cells are important in the development and progression of acute and chronic myeloid and lymphoid leukemia and myelodysplasia. We propose to use in vitro and in vivo approaches to study in depth three cell-free inhibitory activities we have recently reported. Two are probably involved in the pathogenesis of leukemia and myelodysplasia. Large numbers of patients will be screened for the presence of these cell-derived inhibitory activities and for the response of normal and patient stem cells to these activities. This may allow us to detect residual leukemic cells during remission and may be a sensitive means to detect acceleration to the terminal phases of acute leukemia. Animal models will be developed to determine the in vivo significance of these phenomena. Biophysical and immunological cell-separation procedures will be used to further elucidate the cells elaborating the inhibitors. The activities will be purified, and characterized, and radioimmunoassays will be developed. A knowledge of the cells and inhibitory molecules involved will allow us to develop methods in an attempt to counteract the "pathological" and enhance normal interactions in vitro and in vivo.